Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer.

Authors:
Jennifer C Villa
Jennifer C Villa
Weill Graduate School of Medical Sciences of Cornell University
United States
Danica Chiu
Danica Chiu
Memorial Sloan-Kettering Cancer Center New York
Alissa H Brandes
Alissa H Brandes
University of California at San Francisco
United States
Freddy E Escorcia
Freddy E Escorcia
National Institutes of Health
United States
Carlos H Villa
Carlos H Villa
Memorial Sloan Kettering Cancer Center
United States
William F Maguire, PhD
William F Maguire, PhD
Tri-Institutional MD-PhD Program
MD-PhD Candidate
New York, NY | United States
Dr. Cheng-Jun Hu, PhD
Dr. Cheng-Jun Hu, PhD
University of Colorado
Associate Professor
Pulmonary hypertension
Aurora, CO | United States

Cell Rep 2014 Aug 14;8(4):1077-92. Epub 2014 Aug 14.

Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA. Electronic address:

γ-Secretase is composed of four proteins that are obligatory for protease activity: presenilin, nicastrin, Aph1, and Pen-2. Despite the progress toward understanding the function of these individual subunits, there is no information available pertaining to the modulation of γ-secretase in response to environmental changes in cells. Here, we show that hypoxia upregulates γ-secretase activity through a direct interaction with Hif-1α, revealing an unconventional function for Hif-1α as an enzyme subunit, which is distinct from its canonical role as a transcription factor. Moreover, hypoxia-induced cell invasion and metastasis are alleviated by either γ-secretase inhibitors or a dominant-negative Notch coactivator, indicating that γ-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals a mechanism in which γ-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1α, under select physiological and pathological conditions.

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http://dx.doi.org/10.1016/j.celrep.2014.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346175PMC
August 2014
18 Reads
26 Citations
7.210 Impact Factor

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